Ethynylbenzenes

ABSTRACT

Novel process for preparing ethynylbenzene compounds by the dehalogenation of β,β,α-trichlorophenylethane compounds is described. Novel intermediates are also disclosed.

This invention describes a novel process of preparing ethynylbenzenecompounds and derivatives represented by the generic structure which isdescribed by the general formula I; ##SPC1##

where:

R is

Alkyl,

Cycloalkyl,

Alkylcycloalkyl,

Aryl or

Substituted aryl where the substituent is Y"; and

Y, Y' and Y" are hydrogen,

Alkyl,

Halo,

Nitro,

Amino,

Acylamino,

Mono and diloweralkylamino,

Mercapto,

Acylthio,

Loweralkylthio

Loweralkylsufinyl,

Loweralkylsulfonyl,

Hydroxy,

Loweralkoxy,

Acyloxy,

Haloloweralkyl,

Cyano or

Acetyl.

The para position is the preferred position for the R substituents.

The meta position is the preferred position for the Y and Y'substituents, and the ortho position is the preferred position for theY" substituents.

More specifically, this invention describes a process for preparingchemical compounds which have the preferred chemical structuresdescribed by formulae II-IV: ##SPC2##

where Alk is alkyl having 3-7 carbon atoms. ##SPC3##

Where x is 0-2. ##SPC4##

Those compounds which are even more preferred are described by formulaeII-III:

where:

Y is

Hydrogen,

Halo,

Nitro,

Cyano,

Loweralkylsulfonyl or

Haloloweralkyl; and

X = 1.

The more preferred compounds of formula IV are those where Y" is halo.

Compounds which are most preferred are those where Y is halo and chlorois particularly preferred.

In the descriptive portions of this invention the following definitionsapply:

"Alkyl" refers to a loweralkyl hydrocarbon group containing from 1 toabout 7 carbon atoms which may be straight chained or branched."Alkenyl" refers to an unsaturated or partially unsaturated hydrocarbongroup containing from 2 to about 7 carbon atoms which may be straightchained or branched.

"Cycloalkyl" refers to a hydrocarbon ring having up to about sevencarbon atoms.

"Aryl" refers to any benzenoid or non-benzenoid aromatic group butpreferably phenyl.

"Alkoxy" refers to a loweralkoxy group containing from 1 to about 6carbon atoms which may be straight chained or branched.

"Acyl" refers to any organic radical derived from an organic acid by theremoval of its hydroxyl group such as formyl, acetyl, propionyl.

The compounds of this invention may be prepared by the followingprocess.

A Friedel-Crafts reaction of a substitutedbenzene and acetyl chlorideresults in the preparation of a p-substitutedacetophenone. The resultantacetophenone may then be (a) halogenated, (b) nitrated or (c) alkylatedto obtain the corresponding 3-halo, 3-nitro, or3-alkyl-4-substituted-acetophenones. Chlorination or bromination may becarried out in the presence of a small amount of iodine dissolved in aninert solvent such as carbon tetrachloride. A solution of chlorine orbromine is then added while the temperature is held near 0°C. Nitrationis carried out with fuming nitric acid at about 0°C. Alkylation iscarried out under Friedel-Crafts conditions with an alkyl halide andaluminum chloride. The following reaction equations illustrate thesemethods. ##SPC5##

where R is as described above and Hal is chloro or bromo.

Appropriately desired end products having various Y and Y' substituentscan be prepared by using suitable reactions in order to convert onegroup to another. Thus, for example, a 3-halo-4-substituted-acetophenonein which halo is chloro or bromo may be

a. reacted with cuprous cyanide in quinoline at about 150°C to produce a3-cyano-4-substitutedacetophenone.

b. reacted with trifluoromethyliodide and copper powder at about 150°Cin dimethylformamide to obtain a3-trifluoromethyl-4-substituted-acetophenone [as described inTetrahedron Letters: 47, 4095 (1959 )];

c. reacted with cuprous methanesulfinate in quinoline at about 150°C toobtain a 3-methylsulfonyl-4-substitutedacetophenone. A3-nitro-4-substitutedacetophenone may be selectively hydrogenated to thecorresponding amine. A 3-amino-4-substitutedacetophenone may then be

a. mono- or dialkylated with loweralkyl halides or sulfates or acylatedwith loweracyl chlorides or anhydrides;

b. diazotized to the diazonium fluoroborate which is then thermallydecomposed to the 3-fluoro-4-substitutedacetophenone;

c. diazotized and heated in an aqueous medium to form the3hydroxy-4-substitutedacetophenone or heated in an alcohol to form the3-alkoxy-4-substitutedacetophenone. The hydroxyl group may also bealkylated with loweralkyl halides or sulfates to the alkoxyl group oracylated with loweracyl chlorides or anhydrides to the acyloxy compoundin the presence of a tertiary amine such as pyridine;

d. diazotized followed by a Sandmeyer type reaction to yield the halogroup;

e. diazotized and heated with an aqueous solution of potassium iodide toprepare the 3-iodo-4-substitutedacetophenone;

f. diazotized and followed by addition of cuprous cyanide to obtain the3-cyano-4-substitutedacetophenone which in turn may be esterified withan alcohol or hydrolyzed to the amide or carboxylic acid of theacetophenone;

g. diazotized followed by reaction with potassium ethylxanthate followedby hydrolysis to obtain 3-mercapto-4-substitutedacetophenone which canbe esterified to a 3-mercapto-4-substitutedacetophenone. This in turncan be lower alkylated to the lower alkylthio and oxidized to theloweralkylsulfinyl and loweralkylsulfonyl groups or acylated to theacylthio compounds.

A second nitration or halogenation may be carried out on the3-substitutedacetophenone. This may be carried out at any appropriatestage of the synthesis in order to obtain the desired substituents.Thus, for example, a 3-chloro-4-substitutedacetophenone may be nitratedas above to obtain a 3-chloro-5-nitro-4-substitutedacetophenone.Halogenation of a 3-chloroacetophenone gives a 2,5-disubstitutedcompound.

A 3-nitro-4-substitutedacetophenone can be nitrated to give a3,5-dinitro-4-substitutedacetophenone.

Controlled halogenation of the substitutedacetophenone is carried outusing elemental halogen such as chlorine in the presence of a smallamount of iodine and dissolved in an inert solvent such as carbontetrachloride while the temperature is held near 0°C. When thesubstituent desired in the 3-position of the phenyl ring is also achloro group then the starting material is the substituted acetophenone.This results in the additional chlorination at the 3-position. ##SPC6##

Sodium borohydride reduction of the halogenated acetophenone yields thecorresponding benzyl alcohol. This reduction may also be carried out bycatalytic hydrogenation provided the groups present are not sensitive tothis reaction. ##SPC7##

The latter benzyl alcohol may next be treated with a halogenating agentsuch as phosphorus trihalide, phosphorus pentahalide, phosphorusoxyhalide, sulfurylhalide, thionylhalide or sulfur halide to obtain thecorresponding β,β,α-trichlorophenylethane product. ##SPC8##

Elimination of chlorine using methyl lithium or the like such as alkyllithium, or alkyl sodium, or sodamide, or lithium diisopropylamideresults in the desired ethynylbenzene compounds. This is preferablycarried out in an inert atmosphere and lower temperatures and mayinvolve stepwise elimination. ##SPC9##

The final products of this invention and their preparation are disclosedand claimed in Belgian Patent No. 809,147.

These compounds are most useful since they provide significanteffectiveness as anti-inflammatory agents as well as manifestingdesirable analgesic and anti-pyretic properties.

The instant process provides the advantages that the compounds areprepared from more readily accessible agents which are economicallyuseful. The reaction steps involved are relatively routine compared tothe more complex synthesis previously described. This results in theadvantage of elimination of costly equipment and labor.

The various Y, Y', and Y" substituents may also be prepared at varioussteps of the synthesis as previously described. Thus, halogenation ornitration may be carried out on the substituted benzylalcohol or β ,β,α-trichlorophenylethane products.

EXAMPLE 1 3-Chloro-4-cyclohexyl-1-ethynylbenzene

A. p-Cyclohexylacetophenone

To a suspension of anhydrous aluminum chloride (467 g,; 3.5 moles) incarbon tetrachloride (2 l.) is added acetyl chloride (275 g.; 249 cc.,3.5 moles) during fifteen minutes with vigorous stirring and cooling inan ice-bath. Cyclohexylbenzene (481 g,; 3.0 moles) is added dropwiseover a period of three hours, keeping the temperature below 5°. Afteraddition is complete, the product is stirred for another hour beforehydrolyzing by pouring into ice and hydrochloric acid with stirring. Theorganic phase is washed with successive portions of dilute hydrochloricacid, sodium carbonate, and water, and distilled to givep-cyclohexylacetophenone, (b.p. 88°-95.5°/0.05 mm.)

When cyclohexylbenzene in the above example is replaced withcyclopentylbenzene, cycloheptylbenzene, 2'-methylcyclohexylbenzene,i-propylbenzene, i-butylbenzene, and t-butylbenzene, then the productsprepared are p-cyclopentylacetophenone, p-cycloheptylacetophenone,p-(2'methylcyclohexyl)acetophenone, p-i-propylacetophenone,p-i-butylacetophenone and p-t-butylacetophenone.

α,α,3-Trichloro-4-cyclohexylacetophenone

To p-cyclohexylacetophenone (50.5 g.; 0.25 moles) dissolved in carbontetrachloride (300 cc) at ice-bath temperature is added Cl₂ (0.25 moles)dissolved in carbon tetrachloride. Then, iodine (3.9g.) is addedfollowed by excess chlorine dissolved in carbon tetrachloride. Thereaction mixture is allowed to come to room temperature overnight. Thesolvent is removed and the residue is taken up in ether and washed with10% NaHSO₃, saline, and dried with (Na₂ SO₄). The solvent is removed andthe residue distilled to give α,α,3-trichloro-4-cyclohexylacetophenone.

When p-cyclohexylacetophenone is replaced in the above example by theacetophenones of part A, then the products prepared are shown in TableI, below.

TABLE I

α,α,3-trichloro-4-cyclopentylacetophenone

α,α,3-trichloro-4-cycloheptylacetophenone

α,α,3-trichloro-4-(2'-methylcyclohexyl)acetophenone

α,α,3-trichloro-4-i-propylacetophenone

α,α,3-trichloro-4-i-butylacetophenone

α,α,3-trichloro-4-t-butylacetophenone

C. β,β-dichloro-α-(3-chloro-4-cyclohexylphenyl)ethanol

To α,α,3-trichloro-4-cyclohexylphenylacetophenone (68.6 g.; 0.22 moles)in isopropanol (500cc) is added sodium borohydride (2.6 g.: 20% excess)in successive portions. The reaction mixture is heated to 60° andallowed to come to room temperature over several hours with stirring.The reaction mixture is diluted with water and acidified with 10%hydrochloric acid (40 cc) and then extracted into ether. The etherealfraction is washed with water, 10% NaHCO₃, and saline until the washingsare neutral. The organic phase is dried over Na₂ SO₄ and the solventremoved to give β,β-dichloro-α-(3-chloro-4-cyclohexylphenyl)ethanol.

When α,α,3-trichloro-4-cyclohexylphenylacetophenone is replaced in theabove example by the acetophenones of Table I then the correspondingbenzylalcohol of Table II, below, is prepared.

TABLE II

β,β-dichloro-α-(3-chloro-4-cylopentylphenyl)ethanol.

β,β-dichloro-α-(3-chloro-4-cycloheptylphenyl)ethanol.

β,β-dichloro-α-[3-chloro-4-(2'methylcyclohexyl)phenyl] ethanol.β,β-dichloro-α-(3-chloro-4-i-propylphenyl)ethanol.

β,β-dichloro-α-(3-chloro-4-i-butylphenyl)ethanol.

β,β-dichloro-α-(3-chloro-4-t-butylphenyl)ethanol.

D. β,β,α,3-Tetrachloro-4-cyclohexylphenylethane

β,β-Dichloro-α-(3-chloro-4-cyclohexylphenyl)ethanol (67.5 g.; 0.22moles) is heated with thionyl chloride (110 ml) containing 1 drop ofpyridine until solution is obtained. The heating is discontinued and thereaction is allowed to proceed at room temperature for 12 hours. Thereaction mixture is heated for an additional hour and the thionylchloride removed, chased by benzene several times and distilled to giveβ,β,α,3-tetrachloro-4-cyclohexylphenylethane.

When β,β-dichloro-α-(3-chloro-4-cyclohexylphenyl)ethanol in the aboveexample is replaced by the phenyl ethanols of Table II, then thecorresponding tetrachloro compound of Table III below is prepared.

TABLE III

β,β,α,3-tetrachloro-4-cyclopentylphenylethane

β,β,α,3-tetrachloro-4-cycloheptylphenylethane

β,β,α,3-tetrachloro-4-(2'-methylcyclohexyl)phenylethane

β,β,α,3-tetrachloro-4-i-propylphenylethane

β,β,α,3-tetrachloro-4-i-butylphenylethane

β,β,α,3-tetrachloro-4-t-butylphenylethane

E. 3-Chloro-4-cyclohexyl-1-ethynylbenzene

β.β,α,3-tetrachloro-4-cyclohexylphenylethane (55.8 g.; 0.17 moles) isdissolved in anhydrous ether (100 ml). The solution is cooled in anice-bath with stirring under nitrogen. Methyl lithium (2.3 M in ether;300 cc) is added dropwise and the mixture stirred in the icebath for 2.5hours before destroying the excess methyl lithium with ice. The etherealfraction is washed thoroughly with saline until the washings areneutral. Removal of solvent gives 3-chloro-4-cyclohexyl-1-ethynylbenzene(b.p. 82°-88°/0.15 m).

When β,β,α,3-tetrachloro-4-cyclohexylphenylethane in the above exampleis replaced by the tetrachloro compounds of Table III, then thecorresponding ethynylbenzene of Table IV below is prepared.

TABLE IV

3-chloro-4-cyclopentyl-1-ethynylbenzene

3-chloro-4-cycloheptyl-1-ethynylbenzene

3-chloro-4-(2'-methylcyclohexyl)-1-ethynylbenzene

3-chloro-4-i-propyl- 1-ethynylbenzene

3-chloro-4-i-butyl-1-ethynylbenzene

3-chloro-4-t-butyl-1-ethynylbenzene

When methyl lithium in the above reactions is replaced by an equimolaramount of an alkyl lithium reagent, lithium diisopropylamide intetrahydrofuran or NaNH₂ in liquid ammonia then the same products areprepared.

EXAMPLE 2 3-Nitro-4-cyclohexyl-1-ethynylbenzene

A. 3-Nitro-4-cyclohexylacetophenone

Ethyl p-cyclohexylacetophenone (0.066 mole) is added to ice-coldconcentrated sulfuric acid (18 ml) and stirred with cooling for 5minutes. Concentrated nitric acid (Sp. G. 1.51) (2.5 ml) is addeddropwise, maintaining the temperature between 30° and 40° by watercooling when necessary. After addition of the nitric acid is complete,the mixture is stirred for 1/2 hour, then poured into water. The mixtureis made alkaline with sodium hydroxide, then extracted with ether. Theether extract is washed, dried over sodium sulfate, evaporated and theresidue is fractionally distilled to obtain3-nitro-4-cyclohexylacetophenone.

When the acetophenones of Example 1 are used in place ofp-cyclohexylphenylacetophenone in the above example, then thecorresponding nitrated product is prepared.

When 3-nitro-4-cyclohexylacetophenone is used in place ofp-cyclohexylacetophenone in part A of Example 1, and the correspondingreactions are carried out according to parts B-E of Example 1, then theproduct obtained is 3-nitro-4-cyclohexyl-1-ethynylbenzene.

When the acetophenones of Example 1 are used in the above example andthen the corresponding reactions are carried out according to parts A-Eof Example 1, the products obtained are listed in Table IV below.

Table IV

3-nitro-4-cyclopentyl-1-ethynylbenzene

3-nitro-4-cycloheptyl-1-ethynylbenzene

3-nitro-4-(2'-methylhexyl)-1-ethynylbenzene

3-nitro-4-i-propyl-1-ethynylbenzene

3-nitro-4-i-butyl-1-ethynylbenzene

3-nitro-4-t-butyl-1-ethynylbenzene

3-nitro-1-ethynylbiphenyl

EXAMPLE 3

When cyclohexylbenzene is replaced in Example 1 by an equimolar amountof biphenyl and reaction steps A-E are followed accordingly, then theproduct prepared is p-biphenylacetylene (m.p. 81-83.5°C).

EXAMPLE 4

When cyclohexylbenzene is replaced in Example 1 by an equimolar amountof 2-chlorobiphenyl and reaction steps A-E are followed accordingly,then the product prepared is 2'-chloro-4-ethynylbiphenyl.

Calc'd: C=79.06; H=4.27; Cl=16.67; Found: C=78.86; H=4.28; Cl=16.61

EXAMPLE 5

Compounds having the desired, R, Y, Y' and Y" substituents may becarried out accordingly.

We claim:
 1. A compound of the formula: ##SPC10##where X is 0-2 and Y ishalo.
 2. A compound of claim 1 where Y is chloro.
 3. The compound ofclaim 2 which is β,β-dichloro-α-(3-chloro-4-cyclopentylphenyl)ethanol.4. The compound of claim 2 which isβ,β-dichloro-α-(3-chloro-4-cyclohexylphenyl)ethanol.
 5. The compound ofclaim 2 which is β,β-dichloro-α-(3-chloro-4-cycloheptylphenyl)ethanol.6. The compound of claim 2 which isβ,β-dichloro-α-[3-chloro-4-(2'methylcyclohexyl)phenyl]ethanol.